The search continues for a safe and effective topical anesthetic preparation that can ease the pain during dermal procedures, such as venipuncture, intravenous cannulation, punch biopsy and other small incisions, vaccination, and circumcision. A preparation that is safe for use in newborns is especially needed, since circumcision remains a common medical procedure performed on newborns, and existing scientific evidence demonstrates potential medical benefits of newborn male circumcision. Unfortunately, circumcision of infants is typically performed without any pain-relief treatment even though the American Academy of Pediatrics recommends procedural analgesia (AAP Circumcision Policy Statement, March 1999, pp. 686-693) because safe and effective topical preparations are not currently available.
EMLA cream (Astra Pharmaceuticals, Inc., Westboro, Mass.), a eutectic mixture of lidocaine 2.5% and prilocaine 2.5% in an emulsified topical cream (U.S. Pat. No. 4,562,060; U.S. Pat. No. 4,529,601), is the only topical anesthetic product currently marketed in many countries, including the United States, for use on intact skin. Because EMLA cream contains a relatively high concentration of local anesthetic in its oil phase, it exhibits improved efficacy on intact skin compared with other conventional local anesthetic formulations, which are effective only on mucous membranes.
Metabolites of prilocaine, however, are known to be responsible for methemoglobinemia, a serious condition characterized by the ferric form of hemoglobin with impaired oxygen-carrying capacity (B. Jakobson et al., Acta Anaesthesialogica Scandinavica 29: 453-455 (1985)). As a result, the use of EMLA in young children has been severely restricted. For example, in the United States, EMLA is currently contraindicated in infants under 3 months old (M. Buckley et al., Drugs 46:126-151 (1993)), and in infants up to 1 year of age who are also receiving methemoglobin-inducing agents (Physician's Desk Reference, 49.sup.th Ed., Medical Economics Data Production Company, Montvale, N.H. (1995)). In the United Kingdom, EMLA is not approved for use in children under 1 year of age (S. Russell et al., Drug Safety 16:279-287 (1997)). Also, the Drug Information Handbook, 4.sup.th Ed. (1996-1997), published by the American Pharmaceutical Association, states that EMLA cream should not be used in infants under the age of 1 month. Very young patients, and patients with glucose-6-phosphate deficiencies, show increased susceptibility to methemoglobinemia.
Lidocaine, on the other hand, is safe and is the most widely used local anesthetic agent. However, due to low permeability of lidocaine through the stratum corneum, the efficacy of lidocaine alone for topical anesthesia through intact skin has to date been extremely disappointing. Conventional lidocaine creams may be readily prepared by simply dissolving lidocaine in a suitable pharmaceutical oil and emulsified, but these creams can not effectively deliver lidocaine for transdermal anesthesia on intact skin. Efficacy can only be achieved when the concentration of lidocaine in the topical formulation is unacceptably high (e.g., greater than about 30% by weight), posing a risk of systemic toxicity. Limited by the intrinsic solubility of lidocaine in pharmaceutical oils, lidocaine concentration in the oil phase of conventional creams cannot reach the concentration that is necessary for effective transdermal delivery.
EMLA cream achieves higher concentrations of lidocaine in the oil phase compared to other creams by including prilocaine in the formulation, thereby facilitating the solid to oil phase transition of lidocaine. The resulting eutectic mixture has a lidocaine:prilocaine ratio that ranges from 20:80 to 58:42 (U.S. Pat. No. 4,562,060) and the commercially available product (EMLA) has a lidocaine:prilocaine ratio of 50:50. However, as noted above, prilocaine is known for causing methemoglobinemia in children.
A preparation containing lidocaine but little or no prilocaine would, therefore, have a significant clinical advantage over EMLA and would also expand the use of topical anesthetics in children and particularly in infants and newborns.